Affinage

CDK8

Cyclin-dependent kinase 8 · UniProt P49336

Length
464 aa
Mass
53.3 kDa
Annotated
2026-06-09
100 papers in source corpus 38 papers cited in narrative 37 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 6/6 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

CDK8 is a cyclin-dependent kinase that, together with Cyclin C, MED12 and MED13, forms a reversibly associating kinase module of the Mediator complex governing RNA polymerase II transcription (PMID:8700522, PMID:8730095, PMID:19240132, PMID:23563140). The module exerts dual control: through MED12/MED13 it sterically blocks Pol II recruitment to Mediator independently of CDK8 catalysis (PMID:19240132, PMID:23563140), while CDK8 kinase activity weakens module–Mediator binding to enable Pol II engagement, transcription initiation upon stress, and pause release/elongation of signal-induced genes via recruitment of P-TEFb and BRD4 (PMID:20098423, PMID:33933450, PMID:37378433). Within this module MED12 directly activates CDK8 by wrapping around the kinase and positioning an activation helix that stabilizes the T-loop, a configuration defined by cross-linking MS and cryo-EM and disrupted by recurrent cancer-associated MED12 mutations (PMID:31988137, PMID:33523904). CDK8 phosphorylates a defined set of transcription-factor substrates to shape signaling-driven gene programs: STAT1 S727 to set IFN-γ antiviral responses and restrain NK-cell cytotoxicity (PMID:23352233, PMID:23933255, PMID:29386186), E2F1 S375 to inactivate its transcriptional output and protect β-catenin/TCF transcription (PMID:18794899, PMID:22945643), the Notch ICD PEST domain to promote Fbw7-dependent degradation (PMID:15546612), Cyclin H to repress TFIIH (PMID:10993082), and SREBP to attenuate lipogenic transcription (PMID:26222308, PMID:36305265). CDK8 kinase activity drives β-catenin-dependent transformation in amplified colorectal cancer cells (PMID:18794900) and metabolic gene programs including glycolysis (PMID:29117556), whereas a kinase-independent scaffolding function stabilizes Cyclin C (PMID:11313987, PMID:37378433) and sustains BCR-ABL1+ leukemia (PMID:31628323). Beyond transcription, CDK8 phosphorylates cytoplasmic Drp1 S616 to promote mitochondrial fission, consistent with dual cytoplasmic and nuclear localization (PMID:38637532).

Mechanistic history

Synthesis pass · year-by-year structured walk · 19 steps
  1. 1996 High

    Established CDK8 as a CTD kinase by showing it partners with Cyclin C and phosphorylates the RNA Pol II C-terminal domain, placing it at the heart of the transcription machinery.

    Evidence Co-immunoprecipitation and in vitro kinase assays from cell extracts identifying CDK8–Cyclin C complexes that retain CTD kinase activity

    PMID:8700522 PMID:8730095

    Open questions at the time
    • Did not define which Mediator subunits anchor the kinase
    • No distinction yet between activating and repressive transcriptional roles
  2. 1999 High

    Distinguished CDK8 from the TFIIH kinase CDK7 by demonstrating differing CTD substrate specificity and active-site conformations, arguing CDK8 is a regulatory rather than redundant CTD kinase.

    Evidence In vitro kinase assays with recombinant CTD substrates and small-molecule inhibitor profiling

    PMID:10023686

    Open questions at the time
    • In vivo functional consequence of differential CTD marks not resolved
  3. 2000 High

    Identified Cyclin H as a CDK8 substrate, revealing that CDK8 can repress the TFIIH/CDK7 transcription module by phosphorylation.

    Evidence In vitro kinase assay plus dominant-negative phosphomimic overexpression and transcription assays

    PMID:10993082

    Open questions at the time
    • Physiological contexts requiring Cyclin H phosphorylation not mapped
  4. 2001 High

    Showed CDK8 stabilizes its own partner Cyclin C independently of catalysis, the first evidence of a kinase-independent scaffolding role.

    Evidence Half-life and pulse-chase measurements with proteasome inhibitors and kinase-dead CDK8 co-expression

    PMID:11313987

    Open questions at the time
    • Mechanism of how CDK8 binding blocks Cyclin C ubiquitination unresolved
  5. 2004 High

    Linked CDK8 to signal-specific transcription factor turnover by showing it is recruited by Mastermind to phosphorylate the Notch ICD and trigger its Fbw7-dependent degradation.

    Evidence Recombinant in vitro kinase assay, ChIP, PEST-domain mutagenesis and in vivo degradation assays

    PMID:15546612

    Open questions at the time
    • Whether Mediator association is required for ICD phosphorylation not addressed
  6. 2008 High

    Connected CDK8 to oncogenic Wnt/β-catenin transcription, defining it as a kinase-dependent driver of colorectal cancer at a recurrently amplified locus, in part by phosphorylating E2F1.

    Evidence RNAi screens, copy-number analysis, kinase-dead rescue and cross-species genetic epistasis with reporter assays

    PMID:18794899 PMID:18794900

    Open questions at the time
    • Direct E2F1 phosphosite not yet mapped in this work
    • Full set of β-catenin-dependent CDK8 targets undefined
  7. 2009 High

    Defined the repressive arm of the kinase module, showing MED12/MED13 block Pol II recruitment to Mediator without requiring CDK8 catalysis.

    Evidence Reconstituted in vitro transcription, structural EM and biochemical binding assays of CDK8 subcomplexes

    PMID:19240132

    Open questions at the time
    • How CDK8 activity reverses this repression not yet shown
  8. 2010 High

    Revealed a positive transcriptional role for CDK8 in elongation, linking CDK8-Mediator to P-TEFb/BRD4 recruitment on serum-response genes.

    Evidence CDK8 knockdown, Pol II ChIP, co-IP and RNA analysis in tumor cells

    PMID:20098423

    Open questions at the time
    • Direct elongation-factor substrate of CDK8 not identified
  9. 2012 High

    Pinpointed E2F1 serine 375 as the CDK8 phosphosite that inactivates E2F1 transactivation without affecting DNA binding.

    Evidence In vitro kinase assay, S375A mutagenesis, co-IP and reporter assays

    PMID:22945643

    Open questions at the time
    • In vivo gene targets controlled by this event not fully enumerated
  10. 2013 High

    Established CDK8 as the STAT-TAD kinase controlling IFN-γ responses (STAT1 S727) and immune output, including restraint of NK-cell cytotoxicity.

    Evidence Kinase assays, knockdown plus microarray/ChIP, phospho-specific antibodies, and S727A knock-in mice with tumor challenge

    PMID:23352233 PMID:23933255

    Open questions at the time
    • Relative contribution of STAT3/STAT5 phosphorylation in vivo less defined
  11. 2013 High

    Defined how the kinase module docks onto Mediator and how its abundance is controlled, mapping MED13-dependent middle-module binding and Fbw7-mediated MED13/13L turnover.

    Evidence EM and biochemical binding-competition assays plus co-IP and ubiquitination/degradation assays with Fbw7 loss

    PMID:23322298 PMID:23563140

    Open questions at the time
    • Signals controlling Fbw7 targeting of MED13 in vivo unclear
  12. 2015 High

    Extended CDK8 substrate range to metabolic/developmental transcription factors, identifying SREBP and ecdysone-receptor regulation under nutrient control.

    Evidence Co-IP, mass spectrometry, ChIP and in vivo Drosophila genetics with nutrient manipulation

    PMID:26222308

    Open questions at the time
    • Conservation of SREBP phosphosite to mammals not addressed here
  13. 2017 High

    Tied CDK8 kinase activity to glycolytic gene programs and to signal-specific NFκB elongation, broadening its role in metabolic and inflammatory transcription.

    Evidence Analog-sensitive CDK8 alleles with metabolic phenotyping; ChIP and Pol II CTD phosphorylation analysis with CDK8/19 inhibitors

    PMID:28855340 PMID:29117556

    Open questions at the time
    • Direct metabolic-gene substrates beyond Pol II not defined
  14. 2019 High

    Dissected CDK8 versus CDK19, showing CDK8 kinase activity drives IFN-γ pause release and STAT1 phosphorylation while CDK19 acts as a scaffold, and identified context-specific kinase-independent CDK8 functions in leukemia.

    Evidence GRO-seq/PRO-seq, chemical genetics, selective CDK8/CDK19 knockouts; CDK8 KO vs inhibitor comparison in BCR-ABL1+ B-ALL mouse models

    PMID:31495563 PMID:31628323 PMID:31653719

    Open questions at the time
    • Molecular basis of kinase-independent transcriptional effects in leukemia unresolved
    • Substrate(s) downstream of CDK8 in Foxp3 repression not mapped
  15. 2020 High

    Defined the molecular basis of CDK8 activation, showing MED12 wraps the kinase and positions an activation helix at the T-loop, and that cancer MED12 mutations dysregulate this without losing binding.

    Evidence Cross-linking mass spectrometry, in vitro reconstitution, mutagenesis and inhibitor profiling

    PMID:31988137

    Open questions at the time
    • Dynamics of activation in the intact Mediator-bound state not captured
  16. 2021 High

    Provided the integrated structural and mechanistic model in which cryo-EM defines CKM architecture and CDK8 catalysis weakens CKM–core Mediator binding to license PIC formation and stress-induced activation.

    Evidence Cryo-EM of intact yeast CKM and reconstituted CKM–core Mediator binding/transcription assays with in vivo heat-shock validation

    PMID:33523904 PMID:33933450

    Open questions at the time
    • Equivalent dissociation mechanism not yet demonstrated for human CKM in vivo
  17. 2022 High

    Connected the kinase module to chromatin remodeling and tissue lineage, showing CDK8/19 phosphorylate SWI/SNF and govern enhancer co-localization and intestinal/CFTR programs.

    Evidence Phosphoproteomics, ChIP-seq, single and double CDK8/CDK19 knockouts and inhibitors in intestinal models

    PMID:36006697 PMID:36545778

    Open questions at the time
    • Functional SWI/SNF phosphosites and their direct chromatin consequences not fully resolved
  18. 2023 High

    Comprehensively separated kinase-dependent from kinase-independent functions, confirming CDK8/19 kinase activity drives signal-induced reprogramming while Cyclin C stabilization is kinase-independent.

    Evidence Multi-omic CRISPR KO, kinase-inactive mutants and PROTAC degrader with transcriptomics, proteomics and phosphoproteomics

    PMID:37378433

    Open questions at the time
    • Mechanism by which kinase-independent loss reprograms transcription not fully defined
  19. 2024 High

    Extended CDK8 function beyond the nucleus, identifying cytoplasmic Drp1 S616 phosphorylation that promotes mitochondrial fission and suppresses Pink1-deficiency phenotypes.

    Evidence Drosophila genetics, GFP-tagged endogenous localization, Drp1 phospho-S616 immunoblot and Pink1 genetic epistasis

    PMID:38637532

    Open questions at the time
    • Conservation of cytoplasmic Drp1 phosphorylation to mammalian CDK8 not established
    • How CDK8 partitions between nucleus and cytoplasm unknown

Open questions

Synthesis pass · forward-looking unresolved questions
  • How CDK8 substrate selection, kinase-dependent versus kinase-independent outputs, and subcellular partitioning are coordinated across tissues and disease states remains unresolved.
  • No unified model linking module activation state to specific transcription-factor versus cytoplasmic substrates
  • Mechanism of kinase-independent transcriptional reprogramming undefined
  • Determinants of nuclear vs cytoplasmic CDK8 localization unknown

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0140096 catalytic activity, acting on a protein 6 GO:0016740 transferase activity 4 GO:0140110 transcription regulator activity 4 GO:0098772 molecular function regulator activity 2
Localization
GO:0005634 nucleus 3 GO:0005829 cytosol 1
Pathway
R-HSA-168256 Immune System 5 R-HSA-162582 Signal Transduction 4 R-HSA-74160 Gene expression (Transcription) 4 R-HSA-1430728 Metabolism 3 R-HSA-1643685 Disease 2
Partners
CCNCMED12MED13MED15MTBP
Complex memberships
CDK8 kinase module (CKM)Mediator complex

Evidence

Reading pass · 37 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1996 CDK8 forms a complex with Cyclin C that phosphorylates the carboxy-terminal domain (CTD) of the largest subunit of RNA polymerase II; the complex associates with the large subunit of RNA Pol II in vivo and is found in at least two distinct complexes (>500 kDa and ~170 kDa), both retaining CTD kinase activity. Co-immunoprecipitation, in vitro kinase assay, immunoprecipitation from cell extracts Oncogene High 8700522 8730095
2000 CDK8/Cyclin C phosphorylates Cyclin H (a subunit of TFIIH/CDK7 complex) near its alpha-helical domains, repressing TFIIH's ability to activate transcription and its CTD kinase activity; mimicking this phosphorylation in vivo has a dominant-negative effect on cell growth. In vitro kinase assay, in vivo dominant-negative overexpression, transcription assays Nature High 10993082
1999 Cyclin C/CDK8 and Cyclin H/CDK7/p36 phosphorylate distinct residues on recombinant CTD substrates; CDK8 has different substrate specificity from CDK7, reflected both in vitro and on endogenous RNA Pol II, and the two kinases have diverse active-site conformations as shown by differential sensitivity to small-molecule inhibitors. In vitro kinase assay with recombinant CTD substrates, kinase inhibitor profiling Oncogene High 10023686
2004 Mastermind (MAM) recruits CycC:CDK8 to the HES1 promoter in Notch-signaling cells; purified recombinant CycC:CDK8 phosphorylates the Notch ICD within its TAD and PEST domains; this phosphorylation promotes Fbw7/Sel10 ubiquitin ligase-dependent degradation of the Notch ICD; point mutations in conserved PEST Ser residues prevent CDK8-mediated hyperphosphorylation and stabilize the ICD in vivo. Purified recombinant protein in vitro kinase assay, co-immunoprecipitation, chromatin immunoprecipitation, in vivo phosphorylation/degradation assays, site-directed mutagenesis Molecular cell High 15546612
2008 CDK8 kinase activity is necessary for beta-catenin-driven transcriptional activation and cellular transformation in colorectal cancer cells; CDK8 is located at 13q12.13, a recurrently amplified locus, and its suppression inhibits proliferation in high-CDK8/high-beta-catenin colon cancer cells. RNAi loss-of-function screen, copy number analysis, kinase-dead CDK8 rescue experiments, proliferation assays Nature High 18794900
2008 CDK8 phosphorylates E2F1 and thereby represses E2F1's ability to inhibit beta-catenin/TCF-dependent transcription; elevated CDK8 protects beta-catenin/TCF transcription from E2F1-mediated inhibition. Genetic epistasis in Drosophila and human cells, loss-of-function experiments, reporter assays Nature High 18794899
2009 The CDK8 subcomplex (CDK8, CycC, Med12, Med13) represses transcription by blocking RNA Pol II recruitment to Mediator; the repressive function requires Med12 and Med13 but NOT CDK8 kinase activity; the CDK8 submodule binds the Mediator leg/tail domain via Med13 and its association precludes Pol II recruitment. Reconstituted in vitro transcription system with recombinant/endogenous CDK8 subcomplexes, structural EM, biochemical binding assays Genes & development High 19240132
2010 CDK8 positively regulates transcriptional elongation of serum-response genes; CDK8 depletion does not impair RNA Pol II recruitment or promoter escape but leads to slower elongation complexes with hypophosphorylated Pol II; CDK8-Mediator promotes recruitment of P-TEFb and BRD4 to the elongation complex, and CDK8-Mediator directly interacts with P-TEFb. CDK8 knockdown in human tumor cells, Pol II ChIP, co-immunoprecipitation, RNA analysis Nature structural & molecular biology High 20098423
2012 CDK8 regulates E2F1 transcriptional activity by phosphorylating E2F1 at serine 375 both in vitro and in cells; this phosphorylation requires CDK8 kinase activity; S375 phosphorylation is required for E2F1 interaction with CDK8 and inactivates E2F1 transcriptional activation without affecting E2F1 DNA binding or DP1 interaction. In vitro kinase assay, site-directed mutagenesis (S375A), co-immunoprecipitation, transcriptional reporter assays Oncogene High 22945643
2013 The CDK8 module of Mediator phosphorylates STAT1 S727, STAT3, and STAT5 TAD residues upon promoter binding; CDK8-mediated STAT1 S727 phosphorylation is required for IFN-γ-inducible antiviral responses and positively or negatively regulates over 40% of IFN-γ-responsive genes; RNA Pol II occupancy correlates with CDK8-dependent gene expression changes. CDK8 kinase assay, CDK8 knockdown, microarray, ChIP, phospho-specific antibodies Immunity High 23352233
2013 CDK8-mediated phosphorylation of STAT1 S727 restrains NK cell cytotoxicity; the Stat1-S727A mutation (preventing CDK8 phosphorylation) enhances NK cell cytotoxicity, increases perforin and granzyme B expression, and delays tumor onset in vivo; constitutive phosphorylation of STAT1 S727 depends on CDK8. Phospho-mutant knock-in mice (S727A), CDK8 inhibitor experiments, tumor challenge models, flow cytometry Cell reports High 23933255
2013 The SCF-Fbw7 ubiquitin ligase binds CDK8-Mediator and targets MED13/MED13L for proteasomal degradation; since MED13/13L physically link the CDK8 module to Mediator, Fbw7 loss increases CDK8 module-Mediator association. Co-immunoprecipitation, ubiquitination assays, Fbw7 loss-of-function experiments Genes & development High 23322298
2013 The CKM interacts with the Mediator middle module via Med13; CKM binding interferes with CTD-dependent RNA Pol II binding to a middle-module CTD-binding site, preventing holoenzyme formation; EM and biochemical analyses define the subunit organization of the CKM. Electron microscopy, biochemical binding assays, subunit mapping Nature structural & molecular biology High 23563140
2015 In Drosophila, CDK8-CycC interacts with the ecdysone receptor (EcR)-USP heterodimer; CDK8 and Med14 directly interact with the AF1 domain of EcR; CDK8/CycC levels are regulated by nutrient availability and correlate with EcR activity during the larval-pupal transition; CDK8 phosphorylates SREBP at a conserved threonine residue. Co-immunoprecipitation, mass spectrometry, ChIP, in vivo genetic analysis (cdk8/cycC mutants), nutrient manipulation experiments PLoS biology High 26222308
2015 Skp2 SCF complex ubiquitinates macroH2A1 (mH2A1), leading to its degradation and consequent promotion of CDK8 gene and protein expression; CDK8 in turn facilitates Skp2-mediated p27 ubiquitination and degradation, regulating p27 protein levels. Ubiquitination assays, co-immunoprecipitation, protein degradation assays, in vivo mouse tumor models Nature communications Medium 25818643
2016 Co-crystal structure of CDK8/Cyclin C with selective inhibitors reveals an unusual binding mode: inhibitors make a single H-bond to hinge residue A100, a second H-bond to K252, and a cation-π interaction with R356 in the ATP binding site. X-ray co-crystallography, structure-activity relationship medicinal chemistry ACS medicinal chemistry letters High 26985305
2017 CDK8 kinase activity is required for expression of glycolytic cascade components; CDK8 inhibition impairs glucose transporter expression, glucose uptake, glycolytic capacity and reserve; CDK8 hypomorphic alleles (active-site point mutations sensitive to bulky ATP analogs) were used to confirm kinase-dependent regulation. CDK8 analog-sensitive hypomorphic allele engineering, transcriptome analysis, metabolic assays (glucose uptake, glycolytic capacity) Cell reports High 29117556
2017 CDK8/19 are co-recruited with NFκB to promoters of responsive genes upon NFκB activation; CDK8/19 inhibition suppresses RNA Pol II CTD phosphorylation required for transcriptional elongation in a gene-specific manner, thereby suppressing elongation of NFκB-induced transcription; CDK8/19 selectively regulate newly induced but not basal NFκB-driven transcription. ChIP, RNA Pol II CTD phosphorylation analysis, CDK8/19 inhibitors and shRNA, gene expression analysis Proceedings of the National Academy of Sciences of the United States of America High 28855340
2019 CDK8 (but not CDK19) kinase activity promotes RNA Pol II pause release in response to IFN-γ; CDK8 (but not CDK19) phosphorylates STAT1 during IFN-γ stimulation; CDK19 governs IFN-γ responses through a kinase-independent (scaffolding) function; CDK8 kinase inhibition blocks JAK-STAT pathway TF activation. GRO-seq, PRO-seq, cortistatin A (CKM inhibitor), chemical genetics, CDK8/CDK19 selective knockout and transcriptomics Molecular cell High 31495563
2019 CDK8/19 inhibition or CDK8/CDK19 knockout induces Foxp3 expression in antigen-stimulated T cells in a STAT5-activation-dependent, TGF-β-independent manner; CDK8/19 physiologically represses Foxp3 expression in activated conventional T cells. CDK8/19 inhibitors, CDK8/CDK19 shRNA knockdown/CRISPR knockout, flow cytometry, in vivo immunization models Science immunology High 31653719
2020 The N-terminal segment of MED12 wraps around CDK8 and positions an 'activation helix' close to the T-loop of CDK8 to activate its kinase activity; cancer-associated MED12 activation helix mutations do not diminish MED12 affinity for CDK8 but likely alter activation helix positioning; MED12 binding remodels the CDK8 active site and precludes inhibition by type II kinase inhibitors. In vitro biochemistry, cross-linking mass spectrometry, in vivo studies, kinase inhibitor assays Proceedings of the National Academy of Sciences of the United States of America High 31988137
2020 CDK8 kinase activity is required for Xist-mediated gene silencing and establishment of H3K27me3 (via Ezh2 recruitment) during X inactivation; wild-type but not catalytically inactive CDK8 rescues the Xist silencing defect in Cdk8-mutant mouse ES cells; CDK19 mutation does not affect Xist function. Cdk8 kinase-dead mutant mouse ES cells, Xist inducible system, ChIP for H3K27me3, gene expression analysis Development (Cambridge, England) High 32439758
2021 Recombinant yeast CKM binds core Mediator (cMed) and sterically inhibits cMed binding to the RNA Pol II preinitiation complex in vitro; CDK8 kinase activity weakens CKM-cMed interaction, facilitating CKM dissociation and enabling Mediator to bind the PIC and stimulate transcription initiation; CDK8 kinase activity is required for gene activation during heat shock in vivo but not under steady-state growth. Reconstituted in vitro transcription/binding assay with recombinant CKM, in vivo heat-shock gene activation assays The Journal of biological chemistry High 33933450
2021 Cryo-EM structure of the intact S. cerevisiae CKM redefines CKM architecture: Med12 interacts extensively with CycC and activates CDK8 by stabilizing its T-loop through conserved Med12 residues recurrently mutated in human tumors; Med13 has an Argonaute-like bi-lobal architecture. Cryo-electron microscopy structure determination Science advances High 33523904
2001 CDK8 stabilizes Cyclin C protein in a kinase-independent manner; exogenously expressed Cyclin C is rapidly degraded by the ubiquitin-proteasome pathway but co-expression with either catalytically active or inactive CDK8 strongly stabilizes Cyclin C; stabilization is accompanied by Cyclin C phosphorylation. Half-life measurements, proteasome inhibitor experiments, kinase-dead CDK8 co-expression, pulse-chase Oncogene High 11313987
2007 CDK8 positively regulates transcriptional activation in human cells; a CDK8-containing TRAP/Mediator-like complex (TMLC1, 1.5 MDa) augments transcriptional activation in vitro and phosphorylates RNA Pol II, while a smaller CDK8-containing complex (TMLC2, 1 MDa) represses transcription; CDK8 knockdown prevents transcriptional activation by Gal4-VP16. Affinity purification of CDK8-containing complexes, in vitro transcription assay, CDK8 siRNA knockdown, reporter assay Genes to cells Medium 17212659
2019 CDK8/19-CyclinC binds to a central domain of MTBP (metazoan Sld7); this interaction is required for complete genome duplication in human cells; loss of MTBP binding to CDK8/19-CyclinC causes cells to enter mitosis with incompletely duplicated chromosomes and inaccurate chromosome segregation. Co-immunoprecipitation, MTBP domain deletion mutants, DNA replication assays, cell cycle analysis PLoS biology Medium 30695077
2017 CDK8 loss reduces CDK8-mediated STAT1 phosphorylation in NK cells, increases perforin expression, and enhances NK-cell cytotoxicity; conditional CDK8 deletion in NKp46+ NK cells improves tumor surveillance in multiple in vivo tumor models. Conditional NK-cell-specific CDK8 knockout mice, NK cytotoxicity assays, in vivo tumor models (melanoma, lymphoma, leukemia) Cancer immunology research High 29386186
2019 CDK8 has a kinase-independent role in BCR-ABL1+ B-ALL; CDK8 loss significantly delays leukemia onset and prevents disease maintenance; CDK8 deficiency (but not kinase inhibition) produces pronounced transcriptional changes and sensitizes cells to mTOR inhibition, implicating mTOR pathway deregulation as a consequence of CDK8 loss. CDK8 genetic KO in leukemia mouse models, gene set enrichment analysis, CDK8 kinase inhibitor comparison, mTOR inhibitor sensitivity assays Nature communications High 31628323
2019 CDK8 regulates insulin secretion in pancreatic β cells; OSBPL3 is identified as a CDK8-dependent phosphoprotein acting as a negative regulator of glucose-stimulated insulin secretion; CDK8 ablation also compromises embryonic NPY gene silencing in β cells and leads to de novo neuropeptide expression under oxidative stress. Pancreatic β cell-specific Cdk8 knockout mice, phosphoproteomics, glucose tolerance tests, insulin secretion assays Cell reports Medium 31509750
2022 The Mediator kinase module (CDK8/19) phosphorylates key components of the SWI/SNF chromatin remodeling complex in intestinal epithelial cells; SWI/SNF and MED12-Mediator co-localize at lineage-specifying enhancers in a CDK8/19-dependent manner, regulating intestinal lineage specification. CDK8/CDK19 genetic models and pharmacological inhibitors, phosphoproteomic analysis of SWI/SNF subunits, ChIP-seq for enhancer occupancy The Journal of clinical investigation High 36006697
2022 Combined deletion of CDK8 and CDK19 in intestinal organoids downregulates CFTR expression and suppresses CFTR pathway functionality, causing mucus accumulation and increased goblet cell secretion; individual deletions do not recapitulate this phenotype, indicating functional redundancy. Conditional single and double CDK8/CDK19 KO in intestinal organoids and mice, pharmacological CDK8/19 inhibition, CFTR functional assays, transcriptomics EMBO reports High 36545778
2021 CDK8 in mesenchymal stem cells controls osteoclastogenesis via the CDK8-STAT1-RANKL axis; CDK8 promotes RANKL expression through STAT1, and CDK8 pharmacological inhibition represses MSC-dependent osteoclastogenesis and prevents ovariectomy-induced bone loss in vivo. CDK8 conditional KO in MSCs, CDK8 inhibitor treatment, RANKL/STAT1 pathway analysis, ovariectomy mouse model Stem cell reports Medium 35777359
2024 Drosophila Cdk8 promotes phosphorylation of Drp1 at S616 (required for mitochondrial fission) in the cytoplasm of neurons and muscles; Cdk8 loss causes elongated mitochondria; Cdk8 overexpression suppresses Pink1-deficiency phenotypes (elevated ROS, mitochondrial dysmorphology, behavioral defects); endogenous GFP-tagged Cdk8 localizes to both cytoplasm and nucleus. In vivo Drosophila genetics, live imaging of GFP-tagged Cdk8, Drp1 phospho-S616 immunoblot, Pink1 genetic epistasis, ROS assays Nature communications High 38637532
2022 CDK8 phosphorylates SREBP at a conserved threonine residue (Thr390 in Drosophila) to attenuate lipogenic gene transcription; phosphodeficient SREBP-T390A is more stable and more potent in activating lipogenic genes; six conserved N-terminal residues in SREBP are required for interactions with both Cdk8 and the MED15 Mediator subunit; Cdk8 and MED15 act in concert to regulate SREBP-dependent transcription. In vivo Drosophila phosphomutant analysis, biochemical interaction assays, gene expression analysis of lipogenic genes Disease models & mechanisms Medium 36305265
2023 CDK8/19 kinase activity is required for CDK8/19 to act as positive regulators of signal-induced (serum, NFκB, PKC) transcriptional reprogramming; both CDK8 and CDK19 have qualitatively the same effects on protein phosphorylation and gene expression, with quantitative differences attributable to expression levels; CDK8 and CDK19 protect their binding partner Cyclin C from proteolytic degradation in a kinase-independent manner. CRISPR KO of CDK8 and/or CDK19, CDK8/19 kinase-inactive mutants, CDK8/19 PROTAC degrader, transcriptomics, proteomics, phosphoproteomics Nucleic acids research High 37378433
2015 mTORC1 activation causes reduction of the CDK8-CycC complex in vitro and in mouse liver in vivo; mTORC1 is more active in three NAFLD mouse models, correlating with lower CDK8-CycC abundance and increased lipogenic protein expression, placing CDK8 downstream of mTORC1 in a lipogenesis regulatory pathway. Pharmacological (rapamycin) and genetic mTORC1 activation/inhibition, Western blot for CDK8-CycC, in vivo NAFLD mouse models PloS one Medium 26042770

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2008 CDK8 is a colorectal cancer oncogene that regulates beta-catenin activity. Nature 565 18794900
2004 Mastermind recruits CycC:CDK8 to phosphorylate the Notch ICD and coordinate activation with turnover. Molecular cell 495 15546612
2000 TFIIH is negatively regulated by cdk8-containing mediator complexes. Nature 312 10993082
2010 CDK8 is a positive regulator of transcriptional elongation within the serum response network. Nature structural & molecular biology 298 20098423
2009 The human CDK8 subcomplex is a molecular switch that controls Mediator coactivator function. Genes & development 286 19240132
2008 E2F1 represses beta-catenin transcription and is antagonized by both pRB and CDK8. Nature 264 18794899
2013 CDK8 kinase phosphorylates transcription factor STAT1 to selectively regulate the interferon response. Immunity 234 23352233
2013 A conserved Mediator-CDK8 kinase module association regulates Mediator-RNA polymerase II interaction. Nature structural & molecular biology 188 23563140
2010 CDK8: a positive regulator of transcription. Transcription 174 21327159
1996 Cyclin C/CDK8 is a novel CTD kinase associated with RNA polymerase II. Oncogene 152 8700522
2007 Cdk8 is essential for preimplantation mouse development. Molecular and cellular biology 114 17620419
2019 Conversion of antigen-specific effector/memory T cells into Foxp3-expressing Treg cells by inhibition of CDK8/19. Science immunology 113 31653719
2017 CDK8/19 Mediator kinases potentiate induction of transcription by NFκB. Proceedings of the National Academy of Sciences of the United States of America 110 28855340
2013 CDK8-mediated STAT1-S727 phosphorylation restrains NK cell cytotoxicity and tumor surveillance. Cell reports 108 23933255
1999 Cyclin C/CDK8 and cyclin H/CDK7/p36 are biochemically distinct CTD kinases. Oncogene 104 10023686
2017 Inhibition of CDK8 mediator kinase suppresses estrogen dependent transcription and the growth of estrogen receptor positive breast cancer. Oncotarget 102 28147342
2018 Regulatory functions of the Mediator kinases CDK8 and CDK19. Transcription 101 30585107
2013 The SCF-Fbw7 ubiquitin ligase degrades MED13 and MED13L and regulates CDK8 module association with Mediator. Genes & development 100 23322298
2012 CDK8 maintains tumor dedifferentiation and embryonic stem cell pluripotency. Cancer research 98 22345154
2015 Skp2-macroH2A1-CDK8 axis orchestrates G2/M transition and tumorigenesis. Nature communications 93 25818643
2013 Wogonin induced G1 cell cycle arrest by regulating Wnt/β-catenin signaling pathway and inactivating CDK8 in human colorectal cancer carcinoma cells. Toxicology 92 23907061
2013 The two faces of Cdk8, a positive/negative regulator of transcription. Biochimie 92 24139904
2007 Distinct roles for Mediator Cdk8 module subunits in Drosophila development. The EMBO journal 90 17290221
2010 CDK8 expression in 470 colorectal cancers in relation to beta-catenin activation, other molecular alterations and patient survival. International journal of cancer 88 19790197
2018 Hdac1 Regulates Differentiation of Bipotent Liver Progenitor Cells During Regeneration via Sox9b and Cdk8. Gastroenterology 75 30267710
1996 Drosophila Cdk8, a kinase partner of cyclin C that interacts with the large subunit of RNA polymerase II. Molecular biology of the cell 75 8730095
2019 Transcriptional Responses to IFN-γ Require Mediator Kinase-Dependent Pause Release and Mechanistically Distinct CDK8 and CDK19 Functions. Molecular cell 74 31495563
2017 CDK8 Kinase Activity Promotes Glycolysis. Cell reports 68 29117556
2016 Development of a Potent, Specific CDK8 Kinase Inhibitor Which Phenocopies CDK8/19 Knockout Cells. ACS medicinal chemistry letters 65 26985305
2015 Expression of CDK8 and CDK8-interacting Genes as Potential Biomarkers in Breast Cancer. Current cancer drug targets 63 26452386
2012 CDK8 regulates E2F1 transcriptional activity through S375 phosphorylation. Oncogene 62 22945643
2015 CDK8 kinase--An emerging target in targeted cancer therapy. Biochimica et biophysica acta 60 26006748
2015 Cdk8 deletion in the Apc(Min) murine tumour model represses EZH2 activity and accelerates tumourigenesis. The Journal of pathology 59 26235356
2019 Molecular and in vivo Functions of the CDK8 and CDK19 Kinase Modules. Frontiers in cell and developmental biology 58 30693281
2020 A precisely positioned MED12 activation helix stimulates CDK8 kinase activity. Proceedings of the National Academy of Sciences of the United States of America 57 31988137
2011 Dysregulation of CDK8 and Cyclin C in tumorigenesis. Journal of genetics and genomics = Yi chuan xue bao 55 22035865
2018 Mediator kinase CDK8/CDK19 drives YAP1-dependent BMP4-induced EMT in cancer. Oncogene 54 29780169
2018 CDK8 as a therapeutic target for cancers and recent developments in discovery of CDK8 inhibitors. European journal of medicinal chemistry 54 30594029
2021 CDK8 maintains stemness and tumorigenicity of glioma stem cells by regulating the c-MYC pathway. Oncogene 53 33727660
2020 Selective and Potent CDK8/19 Inhibitors Enhance NK-Cell Activity and Promote Tumor Surveillance. Molecular cancer therapeutics 52 32024684
2021 The Cdk8 kinase module regulates interaction of the mediator complex with RNA polymerase II. The Journal of biological chemistry 49 33933450
2021 Structure and noncanonical Cdk8 activation mechanism within an Argonaute-containing Mediator kinase module. Science advances 48 33523904
2019 Identifying Cancers Impacted by CDK8/19. Cells 47 31382571
2021 Loss of Cyclin C or CDK8 provides ATR inhibitor resistance by suppressing transcription-associated replication stress. Nucleic acids research 43 34329458
2010 Role of CDK8 and beta-catenin in colorectal adenocarcinoma. Oncology reports 42 20514474
2023 CDK8 and CDK19: positive regulators of signal-induced transcription and negative regulators of Mediator complex proteins. Nucleic acids research 41 37378433
2020 Capsaicin suppresses breast cancer cell viability by regulating the CDK8/PI3K/Akt/Wnt/β‑catenin signaling pathway. Molecular medicine reports 41 33173974
2019 Inhibition of Cdk8/Cdk19 Activity Promotes Treg Cell Differentiation and Suppresses Autoimmune Diseases. Frontiers in immunology 41 31552016
2019 Systemic Toxicity Reported for CDK8/19 Inhibitors CCT251921 and MSC2530818 Is Not Due to Target Inhibition. Cells 41 31717492
2018 CDK8/19 inhibition induces premature G1/S transition and ATR-dependent cell death in prostate cancer cells. Oncotarget 41 29568371
2007 A kinase subunit of the human mediator complex, CDK8, positively regulates transcriptional activation. Genes to cells : devoted to molecular & cellular mechanisms 40 17212659
2019 A kinase-independent role for CDK8 in BCR-ABL1+ leukemia. Nature communications 39 31628323
2018 NK Cell-Specific CDK8 Deletion Enhances Antitumor Responses. Cancer immunology research 39 29386186
2015 CDK8-Cyclin C Mediates Nutritional Regulation of Developmental Transitions through the Ecdysone Receptor in Drosophila. PLoS biology 38 26222308
2019 CDK8-Novel Therapeutic Opportunities. Pharmaceuticals (Basel, Switzerland) 37 31248103
2009 Revving the Throttle on an oncogene: CDK8 takes the driver seat. Cancer research 37 19808961
2020 Angel or Devil ? - CDK8 as the new drug target. European journal of medicinal chemistry 35 33257171
2016 Discovery of potent and selective CDK8 inhibitors from an HSP90 pharmacophore. Bioorganic & medicinal chemistry letters 34 26852363
2001 Human cyclin C protein is stabilized by its associated kinase cdk8, independently of its catalytic activity. Oncogene 34 11313987
2022 Inhibition of CDK8/19 Mediator kinase potentiates HER2-targeting drugs and bypasses resistance to these agents in vitro and in vivo. Proceedings of the National Academy of Sciences of the United States of America 33 35914167
2013 Emerging roles of Cdk8 in cell cycle control. Biochimica et biophysica acta 33 23643644
2021 The Inhibition of CDK8/19 Mediator Kinases Prevents the Development of Resistance to EGFR-Targeting Drugs. Cells 29 33445730
2017 Structures of the K35 and K15 capsular polysaccharides of Acinetobacter baumannii LUH5535 and LUH5554 containing amino and diamino uronic acids. Carbohydrate research 29 28578199
2023 Discovery of LL-K8-22: A Selective, Durable, and Small-Molecule Degrader of the CDK8-Cyclin C Complex. Journal of medicinal chemistry 28 36930701
2018 CDK8 regulates the angiogenesis of pancreatic cancer cells in part via the CDK8-β-catenin-KLF2 signal axis. Experimental cell research 28 29856990
2022 The role of CDK8 in mesenchymal stem cells in controlling osteoclastogenesis and bone homeostasis. Stem cell reports 27 35777359
2019 The Cdk8/19-cyclin C transcription regulator functions in genome replication through metazoan Sld7. PLoS biology 27 30695077
2017 Ectopic expression of Cdk8 induces eccentric hypertrophy and heart failure. JCI insight 27 28768905
2020 New CDK8 inhibitors as potential anti-leukemic agents - Design, synthesis and biological evaluation. Bioorganic & medicinal chemistry 26 32245563
2018 MicroRNA-770 affects proliferation and cell cycle transition by directly targeting CDK8 in glioma. Cancer cell international 26 30524203
2022 A Selective and Orally Bioavailable Quinoline-6-Carbonitrile-Based Inhibitor of CDK8/19 Mediator Kinase with Tumor-Enriched Pharmacokinetics. Journal of medicinal chemistry 25 35114084
2020 Cdk8 is required for establishment of H3K27me3 and gene repression by Xist and mouse development. Development (Cambridge, England) 25 32439758
2015 mTORC1 Down-Regulates Cyclin-Dependent Kinase 8 (CDK8) and Cyclin C (CycC). PloS one 25 26042770
2013 siRNA-mediated silencing of CDK8 inhibits proliferation and growth in breast cancer cells. International journal of clinical and experimental pathology 24 24427329
2017 Design and synthesis of selective CDK8/19 dual inhibitors: Discovery of 4,5-dihydrothieno[3',4':3,4]benzo[1,2-d]isothiazole derivatives. Bioorganic & medicinal chemistry 23 28302507
2023 Loss of miR-26b-5p promotes gastric cancer progression via miR-26b-5p-PDE4B/CDK8-STAT3 feedback loop. Journal of translational medicine 22 36737782
2021 LINC01224 accelerates malignant transformation via MiR-193a-5p/CDK8 axis in gastric cancer. Cancer medicine 21 33655711
2019 Characterizing CDK8/19 Inhibitors through a NFκB-Dependent Cell-Based Assay. Cells 21 31590445
2013 Structural flexibility and functional interaction of Mediator Cdk8 module. Protein & cell 21 24043446
2020 LncRNA HCP5 Regulates Pancreatic Cancer Progression by miR-140-5p/CDK8 Axis. Cancer biotherapy & radiopharmaceuticals 20 32407143
2019 The microRNA-141-3p/ CDK8 pathway regulates the chemosensitivity of breast cancer cells to trastuzumab. Journal of cellular biochemistry 20 31087707
2021 CircFAT1 facilitates cervical cancer malignant progression by regulating ERK1/2 and p38 MAPK pathway through miR-409-3p/CDK8 axis. Drug development research 19 33818788
2021 Triple-negative breast cancer cells rely on kinase-independent functions of CDK8 to evade NK-cell-mediated tumor surveillance. Cell death & disease 19 34689158
2018 A molecular dynamics investigation of CDK8/CycC and ligand binding: conformational flexibility and implication in drug discovery. Journal of computer-aided molecular design 19 29737445
2023 Transcriptome-based chemical screens identify CDK8 as a common barrier in multiple cell reprogramming systems. Cell reports 18 37235474
2021 Potent and orally bioavailable CDK8 inhibitors: Design, synthesis, structure-activity relationship analysis and biological evaluation. European journal of medicinal chemistry 17 33571827
2020 Pathogenesis of CDK8-associated disorder: two patients with novel CDK8 variants and in vitro and in vivo functional analyses of the variants. Scientific reports 17 33067521
2019 CDK8 Regulates Insulin Secretion and Mediates Postnatal and Stress-Induced Expression of Neuropeptides in Pancreatic β Cells. Cell reports 17 31509750
2022 CDK8 and CDK19 regulate intestinal differentiation and homeostasis via the chromatin remodeling complex SWI/SNF. The Journal of clinical investigation 16 36006697
2019 Downregulation of miR‑138‑5p promotes non‑small cell lung cancer progression by regulating CDK8. Molecular medicine reports 16 31638208
2013 CDK8 as the STAT1 serine 727 kinase? JAK-STAT 16 24069555
2024 Cdk8/CDK19 promotes mitochondrial fission through Drp1 phosphorylation and can phenotypically suppress pink1 deficiency in Drosophila. Nature communications 15 38637532
2023 Antimicrobial and Antibiofilm Effect of Bacteriocin-Producing Pediococcus inopinatus K35 Isolated from Kimchi against Multidrug-Resistant Pseudomonas aeruginosa. Antibiotics (Basel, Switzerland) 15 37107038
2019 Cdk8 and Ssn801 Regulate Oxidative Stress Resistance and Virulence in Cryptococcus neoformans. mBio 15 30755515
2023 Transcriptional Antagonism by CDK8 Inhibition Improves Therapeutic Efficacy of MEK Inhibitors. Cancer research 14 36398965
2022 Cdk8 attenuates lipogenesis by inhibiting SREBP-dependent transcription in Drosophila. Disease models & mechanisms 14 36305265
2017 The CDK8 Complex and Proneural Proteins Together Drive Neurogenesis from a Mesodermal Lineage. Current biology : CB 14 28238659
2022 The Candida albicans Cdk8-dependent phosphoproteome reveals repression of hyphal growth through a Flo8-dependent pathway. PLoS genetics 13 34982775
2021 Cdk8 Kinase Module: A Mediator of Life and Death Decisions in Times of Stress. Microorganisms 13 34683473
2022 CDK8 and CDK19 act redundantly to control the CFTR pathway in the intestinal epithelium. EMBO reports 12 36545778

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